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  1 / 1219 MEDLINE  
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[PMID]:29274324
[Au] Autor:Flores-Pérez A; Elizondo G
[Ad] Endereço:Departamento de Biología Celular, CINVESTAV-IPN, Av. IPN 2508, C.P. 07360, México D.F., Mexico.
[Ti] Título:Apoptosis induction and inhibition of HeLa cell proliferation by alpha-naphthoflavone and resveratrol are aryl hydrocarbon receptor-independent.
[So] Source:Chem Biol Interact;281:98-105, 2018 Feb 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Human papilloma viruses 16 and 18 express E6 and E7 oncoproteins. E6 activates and redirects E6-associated protein (E6AP), an E3 ubiquitin ligase. E6AP interacts with Ube2l3, an E2 ubiquitin conjugating enzyme protein (also known as UbcH7), to promote p53 ubiquitination and degradation by the 26S proteasome. Therefore, blocking E6-mediated p53 degradation might be an alternative treatment for cervical cancer. In addition, activation of the aryl hydrocarbon receptor (AHR) induces Ube2l3 expression, resulting in p53 ubiquitination and degradation. The aim of the present study was to determine whether inhibition of AHR in HeLa cells resulted in an increase in p53 and apoptosis along with a decrease in cell proliferation. The results demonstrate that two AHR antagonists, α-naphthoflavone (α-NF) and resveratrol, decreased cell proliferation, arrested cells in the gap 1/synthesis (G1/S) phases, and increased p53 levels and apoptosis. However, knocking out the Ahr gene did not abrogate the effects of α-NF and resveratrol. Moreover, Ahr-null cells presented similar cell proliferation rates and apoptosis levels when compared to control HeLa cells. Taken together, the results indicate that α-NF's and resveratrol's cytostatic and cytotoxic actions, respectively, occur through an AHR-independent mechanism, and that AHR is not required for HeLa cell proliferation.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Benzoflavonas/toxicidade
Proliferação Celular/efeitos dos fármacos
Receptores de Hidrocarboneto Arílico/metabolismo
Estilbenos/toxicidade
[Mh] Termos MeSH secundário: Sistemas CRISPR-Cas/genética
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos
Células HeLa
Seres Humanos
Microscopia Confocal
Receptores de Hidrocarboneto Arílico/antagonistas & inibidores
Receptores de Hidrocarboneto Arílico/genética
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Receptors, Aryl Hydrocarbon); 0 (Stilbenes); 0 (Tumor Suppressor Protein p53); 604-59-1 (alpha-naphthoflavone); Q369O8926L (resveratrol)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171224
[St] Status:MEDLINE


  2 / 1219 MEDLINE  
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[PMID]:28117203
[Au] Autor:Singh H; Singh JV; Gupta MK; Singh P; Sharma S; Nepali K; Bedi PM
[Ad] Endereço:Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
[Ti] Título:Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies.
[So] Source:Bioorg Med Chem Lett;27(4):850-854, 2017 Feb 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A library of forty 7,8-benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase). Among all the synthesized compounds seven benzoflavone derivatives (A-7, A-8, A-10, A-11, A-12, A-13, A-15) exhibited significant inhibition against CEase in in vitro enzymatic assay. Compound A-12 showed the most promising activity with IC value of 0.78nM against cholesterol esterase. Enzyme kinetic studies carried out for A-12, revealed its mixed-type inhibition approach. Molecular protein-ligand docking studies were also performed to figure out the key binding interactions of A-12 with the amino acid residues of the enzyme's active site. The A-12 fits well at the catalytic site and is stabilized by hydrophobic interactions. It completely blocks the catalytic assembly of CEase and prevents it to participate in ester hydrolysis mechanism. The favorable binding conformation of A-12 suggests its prevailing role as CEase inhibitor.
[Mh] Termos MeSH primário: Benzoflavonas/química
Inibidores Enzimáticos/química
Esterol Esterase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Benzoflavonas/síntese química
Benzoflavonas/metabolismo
Sítios de Ligação
Domínio Catalítico
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/metabolismo
Interações Hidrofóbicas e Hidrofílicas
Concentração Inibidora 50
Cinética
Simulação de Acoplamento Molecular
Ligação Proteica
Esterol Esterase/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Enzyme Inhibitors); EC 3.1.1.13 (Sterol Esterase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE


  3 / 1219 MEDLINE  
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[PMID]:27300691
[Au] Autor:Kumar R; Gupta D
[Ad] Endereço:Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, Delhi, India.
[Ti] Título:Identification of CYP1B1-specific candidate inhibitors using combination of in silico screening, integrated knowledge-based filtering, and molecular dynamics simulations.
[So] Source:Chem Biol Drug Des;88(5):730-739, 2016 Nov.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CYP1B1 is a promising drug target for developing novel drugs against hormonal cancers and hypertension. The development of CYP1B1-specific inhibitors is hindered mainly due to non-specific action of known CYP inhibitors. The active site of CYP1B1 is similar to other cytochromes with different substrate preferences rendering a scope to develop specific inhibitors. We have developed a novel in silico approach for design of selective CYP1B1 inhibitors. The approach consists of deriving details of CYP1B1-specific molecular interactions from prior studies, which is used to perform screening of CYP1B1 with NCI compounds. The conventional compound screening is also complemented with the concept of cutoff distance between heme (Fe) and compounds. The binding free energies and HB percentage occupancy calculations of 94 compounds of cluster 1 have verified the docking results using MD. The docking interactions in the active-site cavity of 7 clusters are also taken into account for optimal binding. Hence, we used knowledgebase filtering and MD simulations to enable discovery of selective CYP1B1 inhibitors. The final filtered lead candidates consist of compounds sandwiched between phenylalanine π-π stacking and less than 6 Å from heme (Fe) for enzymatic action. The findings in the study can help development of novel CYP1B1 selective inhibitors.
[Mh] Termos MeSH primário: Citocromo P-450 CYP1B1/antagonistas & inibidores
Inibidores Enzimáticos/química
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Benzoflavonas/química
Benzoflavonas/metabolismo
Sítios de Ligação
Citocromo P-450 CYP1B1/metabolismo
Inibidores Enzimáticos/metabolismo
Seres Humanos
Isoformas de Proteínas/antagonistas & inibidores
Isoformas de Proteínas/metabolismo
Relação Estrutura-Atividade
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Enzyme Inhibitors); 0 (Protein Isoforms); 604-59-1 (alpha-naphthoflavone); EC 1.14.14.1 (CYP1B1 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1B1)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160615
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.12803


  4 / 1219 MEDLINE  
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[PMID]:27253627
[Au] Autor:Pérez Sáez JM; Bussmann LE; Barañao JL; Bussmann UA
[Ad] Endereço:1 Instituto de Biología y Medicina Experimental-CONICET , Buenos Aires, Argentina .
[Ti] Título:Improvement of Chicken Primordial Germ Cell Maintenance In Vitro by Blockade of the Aryl Hydrocarbon Receptor Endogenous Activity.
[So] Source:Cell Reprogram;18(3):154-61, 2016 Jun.
[Is] ISSN:2152-4998
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Primordial germ cells (PGCs) are the undifferentiated progenitors of gametes. Germline competent PGCs can be developed as a cell-based system for genetic modification in chickens, which provides a valuable tool for transgenic technology with both research and industrial applications. This implies manipulation of PGCs, which, in recent years, encouraged a lot of research focused on the study of PGCs and the way of improving their culture. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that besides mediating toxic responses to environmental contaminants plays pivotal physiological roles in various biological processes. Since a novel compound that acts as an antagonist of this receptor has been reported to promote expansion of hematopoietic stem cells, we conducted the present study with the aim of determining whether addition of an established AHR antagonist to the standard culture medium used nowadays for in vitro chicken PGCs culture improves ex vivo expansion. We have found that addition of α-naphthoflavone in culture medium promotes the amplification of undifferentiated cells and that this effect is exerted by the blockade of AHR action. Our results constitute the first report of the successful use of a readily available AHR antagonist to improve avian PGCs expansion, and they further extend the knowledge of the effects of AHR modulation in undifferentiated cells.
[Mh] Termos MeSH primário: Benzoflavonas/farmacologia
Células Germinativas/citologia
Células Germinativas/efeitos dos fármacos
Receptores de Hidrocarboneto Arílico/antagonistas & inibidores
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Galinhas
Feminino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Receptors, Aryl Hydrocarbon); 604-59-1 (alpha-naphthoflavone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160603
[St] Status:MEDLINE
[do] DOI:10.1089/cell.2016.0015


  5 / 1219 MEDLINE  
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[PMID]:27163632
[Au] Autor:Rhon-Calderón EA; Galarza RA; Lomniczi A; Faletti AG
[Ad] Endereço:Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
[Ti] Título:The systemic and gonadal toxicity of 3-methylcholanthrene is prevented by daily administration of α-naphthoflavone.
[So] Source:Toxicology;353-354:58-69, 2016 04 15.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:In the present study, we investigated the effect of 3-methylcholanthrene (3MC) on sexual maturity and the ability of α-naphthoflavone (αNF) to prevent this action. To this end, immature rats were daily injected intraperitoneally with 3MC (0.1 or 1mg/kg) and/or αNF (80mg/kg). Body weight, vaginal opening and estrous cycle were recorded and ovaries were obtained on the day of estrus. Ovarian weight, ovulation rate (measured by the number of oocytes within oviducts), and follicular development (determined by histology) were studied. No differences were found in body weight, ovarian weight, day of vaginal opening, or the establishment of the estrous cycle among the different groups of rats. However, animals treated with 3MC, at both doses, exhibited a lower number of primordial, primary, preantral and antral follicles than controls. Also, 3MC inhibited the ovulation rate and induced an overexpression of both the Cyp1a1 and Cyp1b1 genes, measured by chromatin immunoprecipitation assay. The daily treatment with αNF alone increased the number of follicles in most of the stages analyzed when compared with controls. Moreover, the αNF treatment prevented completely not only the 3MC-induced decrease in all types of follicles but also the 3MC-induced overexpression of Cyp enzymes and the genetic damage in bone marrow cells and oocytes. These results suggest that (i) daily exposure to 3MC during the pubertal period destroys the follicle reserve and alters the ovulation rate; (ii) the 3MC action seems to be mediated by an aryl hydrocarbon receptor-dependent mechanism; (iii) daily administration of αNF has a clear stimulatory action on the ovarian function; and (iv) αNF may prevent both the systemic and gonadal 3MC-induced toxicity.
[Mh] Termos MeSH primário: Benzoflavonas/administração & dosagem
Benzoflavonas/farmacologia
Citocromo P-450 CYP1A1/genética
Citocromo P-450 CYP1B1/genética
Metilcolantreno/toxicidade
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/patologia
Imunoprecipitação da Cromatina
Relação Dose-Resposta a Droga
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Oócitos/efeitos dos fármacos
Oócitos/patologia
Folículo Ovariano/efeitos dos fármacos
Ovulação/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
Receptores de Hidrocarboneto Arílico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Receptors, Aryl Hydrocarbon); 56-49-5 (Methylcholanthrene); 604-59-1 (alpha-naphthoflavone); EC 1.14.14.1 (Cyp1b1 protein, rat); EC 1.14.14.1 (Cytochrome P-450 CYP1A1); EC 1.14.14.1 (Cytochrome P-450 CYP1B1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160511
[St] Status:MEDLINE


  6 / 1219 MEDLINE  
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[PMID]:27113703
[Au] Autor:Wu Q; Ning B; Xuan J; Ren Z; Guo L; Bryant MS
[Ad] Endereço:Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
[Ti] Título:The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity.
[So] Source:Toxicol Lett;253:55-62, 2016 Jun 24.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Amiodarone is a widely used potent antiarrhythmic for the treatment of cardiac disease; however, its use is often discontinued due to numerous adverse effects, including hepatotoxicity. To investigate the role of drug metabolism in this liver toxicity, amiodarone and its major metabolite desethylamiodarone were incubated with HepG2 cells overexpressing a series of cytochrome P450 (CYP) isoforms. Significantly higher cytotoxicity of amiodarone was observed in HepG2 cells overexpressing CYP3A4 or CYP1A1, compared with that observed in empty vector transduced control cells. Further, higher levels of the more potent hepatotoxic metabolite desethylamiodarone were detected in CYP3A4 or CYP1A1 expressed cells. The CYP3A4 inhibitor ketoconazole and the CYP1A1 inhibitor α-naphthoflavone drastically inhibited the metabolism of amiodarone to desethylamiodarone. Along with the inhibition of CYP1A1 or CYP3A4, the cytotoxicity of amiodarone was significantly reduced. These data indicate that the metabolism of amiodarone to desethylamiodarone by CYP1A1 or CYP3A4 plays an important role in the hepatocellular toxicity of amiodarone.
[Mh] Termos MeSH primário: Amiodarona/toxicidade
Antiarrítmicos/toxicidade
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Citocromo P-450 CYP1A1/metabolismo
Citocromo P-450 CYP3A/metabolismo
Hepatócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Ativação Metabólica
Amiodarona/análogos & derivados
Amiodarona/metabolismo
Antiarrítmicos/metabolismo
Benzoflavonas/farmacologia
Sobrevivência Celular/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia
Doença Hepática Induzida por Substâncias e Drogas/genética
Doença Hepática Induzida por Substâncias e Drogas/patologia
Citocromo P-450 CYP1A1/antagonistas & inibidores
Citocromo P-450 CYP1A1/genética
Citocromo P-450 CYP3A/genética
Inibidores do Citocromo P-450 CYP3A/farmacologia
Relação Dose-Resposta a Droga
Células Hep G2
Hepatócitos/enzimologia
Hepatócitos/patologia
Seres Humanos
Cetoconazol/farmacologia
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 0 (Benzoflavones); 0 (Cytochrome P-450 CYP3A Inhibitors); 604-59-1 (alpha-naphthoflavone); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (CYP1A1 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1A1); EC 1.14.14.1 (Cytochrome P-450 CYP3A); M31FU99E3Y (desethylamiodarone); N3RQ532IUT (Amiodarone); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170203
[Lr] Data última revisão:
170203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160427
[St] Status:MEDLINE


  7 / 1219 MEDLINE  
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[PMID]:27112072
[Au] Autor:Wincent E; Kubota A; Timme-Laragy A; Jönsson ME; Hahn ME; Stegeman JJ
[Ad] Endereço:Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden; Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543-1050, USA. Electronic address: emma.wincent@swetox.se.
[Ti] Título:Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner.
[So] Source:Biochem Pharmacol;110-111:117-29, 2016 Jun 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphthoflavone (αNF) and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.
[Mh] Termos MeSH primário: Carbazóis/farmacologia
Citocromo P-450 CYP1A1/genética
Edema/genética
Regulação da Expressão Gênica no Desenvolvimento
Receptores de Hidrocarboneto Arílico/genética
Proteínas de Peixe-Zebra/genética
[Mh] Termos MeSH secundário: Animais
Benzoflavonas/farmacologia
Citocromo P-450 CYP1A1/antagonistas & inibidores
Citocromo P-450 CYP1A1/deficiência
Edema/induzido quimicamente
Edema/metabolismo
Edema/patologia
Embrião não Mamífero
Retroalimentação Fisiológica
Injeções
Morfolinos/genética
Morfolinos/metabolismo
Oligonucleotídeos Antissenso/genética
Oligonucleotídeos Antissenso/metabolismo
Pericárdio/efeitos dos fármacos
Pericárdio/metabolismo
Pericárdio/patologia
Receptores de Hidrocarboneto Arílico/agonistas
Receptores de Hidrocarboneto Arílico/antagonistas & inibidores
Receptores de Hidrocarboneto Arílico/metabolismo
Transdução de Sinais
Peixe-Zebra
Proteínas de Peixe-Zebra/agonistas
Proteínas de Peixe-Zebra/antagonistas & inibidores
Proteínas de Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6-formylindolo(3,2-b)carbazole); 0 (AHR2 protein, zebrafish); 0 (Benzoflavones); 0 (Carbazoles); 0 (Morpholinos); 0 (Oligonucleotides, Antisense); 0 (Receptors, Aryl Hydrocarbon); 0 (Zebrafish Proteins); 604-59-1 (alpha-naphthoflavone); EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160427
[St] Status:MEDLINE


  8 / 1219 MEDLINE  
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[PMID]:27020609
[Au] Autor:Moyer BJ; Rojas IY; Kerley-Hamilton JS; Hazlett HF; Nemani KV; Trask HW; West RJ; Lupien LE; Collins AJ; Ringelberg CS; Gimi B; Kinlaw WB; Tomlinson CR
[Ad] Endereço:Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
[Ti] Título:Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFß, and IDO1.
[So] Source:Toxicol Appl Pharmacol;300:13-24, 2016 Jun 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor ß1 (TGFß1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFß1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.
[Mh] Termos MeSH primário: Compostos Azo/farmacologia
Dieta Ocidental
Cinurenina/biossíntese
Obesidade/prevenção & controle
Pirazóis/farmacologia
Receptores de Hidrocarboneto Arílico/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adiposidade
Animais
Benzoflavonas/farmacologia
Fígado Gorduroso/prevenção & controle
Hepatócitos/efeitos dos fármacos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
Gordura Intra-Abdominal/efeitos dos fármacos
Lipídeos/sangue
Lipoproteínas LDL
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Transdução de Sinais
Receptor 2 Toll-Like/metabolismo
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide); 0 (Azo Compounds); 0 (Benzoflavones); 0 (IDO1 protein, mouse); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Lipids); 0 (Lipoproteins, LDL); 0 (Pyrazoles); 0 (Receptors, Aryl Hydrocarbon); 0 (Toll-Like Receptor 2); 0 (Transforming Growth Factor beta); 0 (oxidized low density lipoprotein); 343-65-7 (Kynurenine); 604-59-1 (alpha-naphthoflavone)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160330
[St] Status:MEDLINE


  9 / 1219 MEDLINE  
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[PMID]:26946220
[Au] Autor:Yauk CL; Buick JK; Williams A; Swartz CD; Recio L; Li HH; Fornace AJ; Thomson EM; Aubrecht J
[Ad] Endereço:Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
[Ti] Título:Application of the TGx-28.65 transcriptomic biomarker to classify genotoxic and non-genotoxic chemicals in human TK6 cells in the presence of rat liver S9.
[So] Source:Environ Mol Mutagen;57(4):243-60, 2016 May.
[Is] ISSN:1098-2280
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In vitro transcriptional signatures that predict toxicities can facilitate chemical screening. We previously developed a transcriptomic biomarker (known as TGx-28.65) for classifying agents as genotoxic (DNA damaging) and non-genotoxic in human lymphoblastoid TK6 cells. Because TK6 cells do not express cytochrome P450s, we confirmed accurate classification by the biomarker in cells co-exposed to 1% 5,6 benzoflavone/phenobarbital-induced rat liver S9 for metabolic activation. However, chemicals may require different types of S9 for activation. Here we investigated the response of TK6 cells to higher percentages of Aroclor-, benzoflavone/phenobarbital-, or ethanol-induced rat liver S9 to expand TGx-28.65 biomarker applicability. Transcriptional profiles were derived 3 to 4 hr following a 4 hr co-exposure of TK6 cells to test chemicals and S9. Preliminary studies established that 10% Aroclor- and 5% ethanol-induced S9 alone did not induce the TGx-28.65 biomarker genes. Seven genotoxic and two non-genotoxic chemicals (and concurrent solvent and positive controls) were then tested with one of the S9s (selected based on cell survival and micronucleus induction). Relative survival and micronucleus frequency was assessed by flow cytometry in cells 20 hr post-exposure. Genotoxic/non-genotoxic chemicals were accurately classified using the different S9s. One technical replicate of cells co-treated with dexamethasone and 10% Aroclor-induced S9 was falsely classified as genotoxic, suggesting caution in using high S9 concentrations. Even low concentrations of genotoxic chemicals (those not causing cytotoxicity) were correctly classified, demonstrating that TGx-28.65 is a sensitive biomarker of genotoxicity. A meta-analysis of datasets from 13 chemicals supports that different S9s can be used in TK6 cells, without impairing classification using the TGx-28.65 biomarker.
[Mh] Termos MeSH primário: Perfilação da Expressão Gênica/métodos
Testes de Mutagenicidade/métodos
Mutagênicos/toxicidade
[Mh] Termos MeSH secundário: Ativação Metabólica/efeitos dos fármacos
Animais
Apoptose/efeitos dos fármacos
Arocloros/toxicidade
Benzoflavonas/toxicidade
Linhagem Celular
Etanol/toxicidade
Marcadores Genéticos
Seres Humanos
Fígado/efeitos dos fármacos
Fenobarbital/toxicidade
Ratos
Transcriptoma/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aroclors); 0 (Benzoflavones); 0 (Genetic Markers); 0 (Mutagens); 3K9958V90M (Ethanol); YQE403BP4D (Phenobarbital)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160307
[St] Status:MEDLINE
[do] DOI:10.1002/em.22004


  10 / 1219 MEDLINE  
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[PMID]:26924701
[Au] Autor:Mu J; Jin F; Wang J; Wang Y; Cong Y
[Ad] Endereço:Key Laboratory for Ecological Environment in Coastal Areas (State Oceanic Administration, SOA), National Marine Environmental Monitoring Center, Dalian, 116023, China.
[Ti] Título:The effects of CYP1A inhibition on alkyl-phenanthrene metabolism and embryotoxicity in marine medaka (Oryzias melastigma).
[So] Source:Environ Sci Pollut Res Int;23(11):11289-97, 2016 Jun.
[Is] ISSN:1614-7499
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) are the predominant form of PAHs in crude oils, of which, 3-5 ring alkyl-PAH may cause dioxin-like toxicity to early life stages of fish. Retene (7-isopropyl-1-methylphenanthrene), a typical alkyl-phenanthrene compound, can be more toxic than phenanthrene, and the mechanism of retene toxicity is likely related to its rapid biotransformation by cytochrome P450 (CYP) enzymes to metabolites with a wide array of structures and potential toxicities. Here, we investigated how α-naphthoflavone (ANF), a cytochrome P450 1A (CYP1A) inhibitor, affected the embryotoxicity of retene and the role that CYP1A inhibition may play in the interactions. Marine medaka (Oryzias melastigma) embryos were exposed, separately or together, to 200 µg/L retene with 0, 5, 10, 100, and 200 µg/L ANF for 14 days. The results showed that ANF significantly inhibited the induction of CYP1A activity by retene; however, ANF interacted with retene to induce significant developmental toxicity and genotoxicity at 10, 100, and 200 µg/L (p < 0.01). Tissue concentrations of retene and its metabolites and lipid hydroperoxide (LPO) activity also increased, whereas the inhibition of the glutathione S-transferase (GST) activity and the alteration in metabolic profiles of retene were observed. The interactions of retene with ANF indicate that CYP1A inhibition was possibly act through different mechanisms to produce similar developmental effects and genotoxicity. Retene metabolites and altered metabolic profile were likely responsible for retene embryotoxicity to marine medaka. Therefore, elevated toxicity of alkyl-phenanthrene under CYP1A inhibitor suggested that the ecotoxicity of PAHs in coastal water may have underestimated the threat of PAHs to fish or ecosystem.
[Mh] Termos MeSH primário: Citocromo P-450 CYP1A1/antagonistas & inibidores
Embrião não Mamífero/efeitos dos fármacos
Oryzias/metabolismo
Fenantrenos/toxicidade
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Animais
Benzoflavonas/farmacologia
Relação Dose-Resposta a Droga
Embrião não Mamífero/anormalidades
Embrião não Mamífero/enzimologia
Glutationa Transferase/metabolismo
Oryzias/embriologia
Petróleo/análise
Petróleo/metabolismo
Fenantrenos/análise
Fenantrenos/farmacocinética
Poluentes Químicos da Água/análise
Poluentes Químicos da Água/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Petroleum); 0 (Phenanthrenes); 0 (Water Pollutants, Chemical); 0W2D2E1P9Q (retene); 604-59-1 (alpha-naphthoflavone); EC 1.14.14.1 (Cytochrome P-450 CYP1A1); EC 2.5.1.18 (Glutathione Transferase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160301
[St] Status:MEDLINE
[do] DOI:10.1007/s11356-016-6098-2



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